CA2123405C - Angiostatic steroids - Google Patents

Angiostatic steroids Download PDF

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Publication number
CA2123405C
CA2123405C CA002123405A CA2123405A CA2123405C CA 2123405 C CA2123405 C CA 2123405C CA 002123405 A CA002123405 A CA 002123405A CA 2123405 A CA2123405 A CA 2123405A CA 2123405 C CA2123405 C CA 2123405C
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diol
pregnadien
dione
steroid
alpha
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CA2123405A1 (en
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Abbot F. Clark
Raymond E. Conrow
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Alcon Research LLC
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Alcon Manufacturing Ltd
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Priority claimed from US07/941,485 external-priority patent/US5371078A/en
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Priority to CA002425846A priority Critical patent/CA2425846A1/en
Priority to CA002425849A priority patent/CA2425849C/en
Priority to CA002425841A priority patent/CA2425841C/en
Publication of CA2123405A1 publication Critical patent/CA2123405A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J11/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J3/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by one carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring the nitrogen atom being directly linked to the cyclopenta(a)hydro phenanthrene skeleton
    • C07J41/0027—Azides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J5/00—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond
    • C07J5/0046—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa
    • C07J5/0053—Normal steroids containing carbon, hydrogen, halogen or oxygen, substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane and substituted in position 21 by only one singly bound oxygen atom, i.e. only one oxygen bound to position 21 by a single bond substituted in position 17 alfa not substituted in position 16
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane

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  • Chemical Kinetics & Catalysis (AREA)
  • Ophthalmology & Optometry (AREA)
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  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
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  • Steroid Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Angiostatic steroids for use in controlling neovascularization and ocular hypertension are disclosed.
Pharmaceutical compositions of the angiostatic steroids and methods for their use in treating neovascularization and ocular hypertension, including controlling the ocular hypertension associated with primary open angle glaucoma, are disclosed. In addition, the combination of the compounds with glucocorticoids for the prevention of elevated intraocular pressure during the treatment of inflammation is disclosed.

Description

ANCIOSTATIC STEROIDS
Background of the I:nvention Field of the Invention This invention relates to angiostatic steroids for controlling ocular hypertension. The compounds are also useful in preventing and treatirig neovascularization. Specifically, the invention is directed to new angiostatic steroids, pharmaceutical compositions comprising the angiostatic steroids, and methods of treatment which comprise administering these compositions to treat ocular hypertension, including controlling ocular hypertension associated with primary open angle glaucoma, and. to treat neovascularization. In addition, the compounds can be used in combination with glucocorticoids to treat ocular inflammation without the significant intraocular pressure rise commonly associated with the use of glucocorticoids.

Description of Related Art Steroids functioning to inhibit angiogenesis in the presence of heparin or specific heparin fragments are disclosed in Crum, et al., A New Class of Steroids Inhibits Angiogenesis in the Presence of Heparin or a Heparin Fragment, Science, Vol.230, pp.1375-1378 (December 20, 1985). The authors refer to such steroids as "angiostatic" steroids. Included within the new class of steroids found to be angiostatic are the dihydro and tetrahydro metabolites of cortisol and cortexolone.
In a follow-up study directed to testing a hypothesis as to the mechanism by which the steroids inhibit angiogenesis, it was shown that heparin/angiostatic steroid compositions cause dissolution of the basement membrane scaffolding to which anchorage dependent endothelia are attached resulting in capillary involution; see, Ingber, et al., A Possible Mechanism la for Inhibition of Angiogenesis by Angiostatic Steroids:
Induction of Capillary Basement Membrane Dissolution, Endocrinology Vol. 119, pp.1768-1775 (1986).

A group cf tetrahydro steroids useful in inhibiting angiogenesis is disclosed in International Patent Publication No. W087/02672 published May 7, 1987, Aristoff, WO 93/10141 PC'1i'/US92/10J~3 et al., (The Upjohn Company). The compounds are disclosed for use in treating head trauma, spinal trauma, septic or traumatic shock, stroke and hemorrhage shock. In addition, the patent application discusses the utility of these compounds in embryo implantation and in the treatment of cancer, arthr-it-is and s arteriosclerosis. Some of the steroids disclosed in Aristoff et al. are disclosed in U.S. Patent No. 4,771,042 in combination with heparin or a heparin fragment for inhibiting angiogenesis in a warm blooded animal.

Compositions of hydrocortisone, "tetrahydrocortisol-S," and U-72,745G, each in combination with a beta cyclodextrin, have been shown to inhibit corneal neovascularization: Li, et al., Angiostatic Steroids Potentiated by Sulphated Cyclodextrin Inhibit Corneal Neovascularization, Investigative Ophthalmology and Visual Science, Vol. 32, No. 11, pp. 2898-2905 (October, 1991). The steroids alone reduce neovascularixation somewhat but are not effective alone in effecting regression of neovascularization.

Tetrahydrocortisol (THF) has been disclosed for its use in lowering the intraocular pressure (IUP) of rabbits made hypertensive with dexamethasone alone, or with dexamethasone/5-beta-dihydrocortisol; see Southren, et al., Intraocular Hypotensive Effect of a Topically Applied Cortisol Metabolite: 3-a7pha, 5-beta-tetrahydrocortisol, Investigative Ophthalmology and Visual Sdience, Vo1.28 (May, 1987). The authors suggest THF inay. be useful as an antiglaucoma agent. In U.S. Patent No. 4,863,912, issued to Southren et al.
on September 5, 1989, pharmaceutical compositions containing THF and a methpd for using these compositions to control intraocular pressure are disclosed.
THF has been disclosed as an angiostatic steroid in Folkman; -et al., Anglostatic Steroids, Ann. Surg., Vo1.206, No.3 (1987) wherein it is suggested angiostatic steroids may have potential use for diseases dominated by abnormal neovascularization, including diabetic retinopathy, neovascular glaucoma and retrolental fibroplasia.

Many compounds classified as glucocorticoids, such as dexamethasone and prednisolone, are very effective in the treatment of inflammed tissues;
however, when these compounds are topically applied to the eye to treat ocular inflammation, certain patients experience elevated intraocular pressure.
Patients who experience these elevations when treated with glucocorticoids are generally referred to as "steroid responders.B: These pressure elevations are of particular concern to patients who already suffer from elevated intraocular pressures, such as glaucoma patients. In addition, there is always a risk that the use of glucocorticoids in patients having normal intraocular pressures will cause pressure rises great enough to damage ocular tissues. Since glucocorticoid therapy is frequently long term (i.e., several days or more), there is potential for significant damage to ocular tissue as a result of prolonged elevations in intraocular pressure attributable to that therapy.

The following articles may be referenced for further background information concerning the well-recognized association betweeri ophthalmic glucocorticoid therapy and elevations in intraocular pressure:

Kitazawa, Increased Intraocular Pressure Induced by Corticosteroids, Am. J. Ophthal., Vol.82 pp.492-493 (1976) ;

Cantrill, et al., Comparison of In Vitro Potency of Corticosteroids with Ability to Raise Intraocular Pressure, Am. J. Ophthal., Vol.79 pp.1012-1016 (1975);
and Mindel, et al., Comparative Ocular Pressure Elevation by Medrysone, Fluorometholone, and Dexamethasone Phosphate, Arch. Ophthal., Vol.98 pp.1577-1578 (1980).

Commonly assigned U.S. Patent No. 4,945,089 discloses the use of the angiostatic steroid tetrahydrocortexolone in combination with a glucocorticoid to treat ocular inflammation without the intraocular pressure elevating effect commonly associated with topical administration of glucocorticoids. In addition, commonly assigned International Publication No.
W091/03245 published on March 21, 1991, discloses the 3a angiostatic steroids of Aristoff, et al. in combination with glucocorticoids tc> treat ocular inflammation without significant increase in intraocular pressure.

Summary of the Invention This invention is directed to angiostatic steroids and methods of using compositions of these steroids in inhibiting neovascularization. The compositions containing the steroids can be used for treatment of angiogenesis dependent diseases, for example: head trauma, spinal trauma, septic or traumatic shock, stroke, hemorrhagic shock, cancer, arthritis, arteriosclerosis, angiofibroma, arteriovenous malformations, corneal graft neovascularization, delayed wound healing, diabetic retinopathy, granulations, burns, hemangioma, hemophilic joints, hypertrophic scars, neovascular glaucoma, nonunion fractures, Osler-Weber Syndrome, psoriasis, pyogenic granuloma, retrolental fibroplasia, pterigium, scleroderma, trachoma, vascular adhesions, and solid tumor growth. In particular, the angiostatic steroids and compositions thereof are useful for controlling ocular neovascularization.

The invention also encompasses methods for controlling ocular hypertension and glaucoma through the systemic or local administration of the compositions disclosed herein.

The present invention also includes the use of the angiostatic steroids in combination with glucocorticoids for the treatment of ocular inflammation. The addition of at least one angiostatic steroid makes it possible to employ the potent antiinflammatory glucocorticoids without producing significant elevations in intraocular pressure.

According to one aspect of the present invention, there is provided topical, systemic or intraocular use of a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of: 4,9(11)-Pregnadien-17a,21-diol-3,20-dione-2l-acetate; 4,9(11)-Pregnadien-17a,21-4a diol-3,20-dione; il-Epicortisol; 17a-Hydroxyprogesterone; and Tetrahydrocortexolone (THS), for preventing or treating ocular neovascularization.

According to another aspect of the present invention, there is provided a commercial package comprising a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of: 4,9(11)-Pregnadien-17a,21-diol-3,20-dione-2l-acetate; 4,9(11)-Pregnadien-17a,21-diol-3,20-dione; 11-Epicortisol; 17a-Hydroxyprogesterone; and Tetrahydrocortexolone (THS), together with instructions for its use in preventing or treating ocular neovascularization.
According to still another aspect of the present invention, there is provided topical, systemic or intraocular use of a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of: 4,9(11)-Pregnadien-17a,21-dio1-3,20-dione-21-acetate; 4,9(11)-Pregnadien-17a,21-diol-3,20-dione; 11-Epicortisol; 17a-Hydroxyprogesterone; and Tetrahydrocortexolone (THS), for preventing or treating ocular neovascularization of tissues in the front or the back of an eye of a host.

According to yet another aspect of the present invention, there is provided a commercial package comprising a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of: 4,9(11)-Pregnadien-17a,21-diol-3,20-dione-2l-acetate; 4,9(11)-Pregnadien-17a,21-diol-3,20-dione; 11-Epicortisol; 17a-Hydroxyprogesterone; and Tetrahydrocortexolone (THS), together with instructions for its use in preventing or treating ocular neovascularization of tissues in the front or the back of an eye of a host.

According to a further aspect of the present invention, there is provided use of a therapeutically effective 4b amount of a composition comprising an ophthalmically acceptable excipient and a compound of the formula:

R3 iz 17 Rlo ~ 1 9 14 15 9 Structure [A]

R3 RIo R13 Rb Structure [B]

wherein Rl is H, (3-CH3 or P-C2H5i R2 is F, C9-C11 double bond, C9-C11 epoxy, H or Cl; R3 is H, OR26, OC (=O) R27, halogen, C9-C11 double bond, C9-C11 epoxy, =0, -OH, -0- alkyl (C1-C12) , -OC (=O) alkyl (C1-C12) ,-OC (=O) N(R) 2 or -OC (=O) OR7, and R is hydrogen, alkyl (C1-C4), or phenyl and each R is the same or different, and R7 is alkyl (Cl-C12) ; R4 is H, CH3, Cl or F; R5 is H, OH, F, Cl, Br, CH3, phenyl, vinyl or allyl; R6 is H or CH3; R9 is CH2CH2OR26, CH2CH2OC (=O) R27, H, OH, CH3, F, =CH2, CHzC (=O) OR28, OR26, O(C=O)R27 or O(C=O) CH2 (C=O) OR26i Rlo is -C=CH, -CH=CH2, halogen, CN, N3, OR26, OC (=0) R27, H, OH, CH3 or Rlo forms a second bond between positions C-16 and C-17; R12 is H or forms a double bond with Rl or R14; R13 is halogen, OR26, OC (=O) R27, NH2, NHR26, NHC (=O)R27, N(R26) 2, NC (=O) R27, N3, H, -OH, =0, -O-P (=O) (OH) z, or -O-C (=O) - (CH2) COOH where t is an integer from 2 to 6; R14 is H or forms a double bond with 4c R12; R15 is H, =0 or -OH; R23 is -OH, O-C (=O) -R11, -OP (O) -(OH) 2, -O-C (=O) -(CH2) tCOOH or R23 with Rlo forms a cyclic phosphate wherein t is an integer from 2 to 6; and R11 is -Y- (CH2) n-X- (CH2) m-SO3H, -Y' - (CH2) p-X' - (CH2) q-NR16R17 or 5-Z(CH2)rQ, wherein, Y is a bond or -0-; Y' is a bond, -0-, or -S-; each of X and X' is a bond, -CON(Rla)-, -N(Rla)CO-, -0-, -S-, -S (0) -, or -S (02) -; R18 is hydrogen or alkyl (C1-C4) ;
each of R16 and R17 is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl; n is an integer of from 4 to 9; m is an integer of from 1 to 5; p is an integer of from 2 to 9; q is an integer of from 1 to 5; Z is a bond or -0-; r is an integer of from 2 to 9; and Q
is one of the following: (1) -R19-CH2COOH, wherein R19 is -S-, -S (0) -, -S (0) 2-, -SO2N(R20) -, or N(R20) SO2-; and R20 is hydrogen or lower alkyl-(C1-C4); with the proviso that the total number of carbon atoms is R20 and (CH2)r is not greater than 10; or (2) -CO-COOH; or (3) CON(R21)CH(R22)COOH, wherein R21 is H and R22 is H, CH3, -CH2COOH, -CH2CH2COOH, -CHzOH, -CH2SH, -CH2CH2SCH3, or -CH2Ph-OH, wherein Ph-OH is p-hydroxyphenyl; or R21 is CH3 and R22 is H; or -N (R21) CH (R22) COOH is -NHCH2CONHCH2COOH; and pharmaceutically acceptable salts thereof; with the proviso that if R23 is a phosphate, it must form a cyclic phosphate, with Rlo when R13 is =0, except for the compound, wherein Rl is (3-CH3, R2 and R3 taken together form a double bond between positions 9 and 11, R4 and R6 are hydrogen, R12 and R14 taken together form a double bond between positions 4 and 5, R5 is a-F, R9 is (3-CH3, Rlo is a-OH, R13 and R15 are =0 and R23 is -OP (O) -(OH) 2;
R24 is C or 0, and there may be a double bond between positions 1 and 2 when R24 is C; R25 is C(R15) CH2-R23, OH, OR26, OC ( =0 ) R2 7, R26, COOH, C ( =O ) OR26 , CHOHCH2OH , CHOHCH2OR26, CHOHCHzOC (=O) R27, CHzCHzOH, CH2N (R26) z, CH2OH, CH2OR26, CH2O (C=O) R27, CH2O (P=O) (OH) z, CH2O (P=O) (OR26) 2, CH2SH, CH2S-R26, 4d CH2SC (=0) R27, CH2NC (0) R27, C(O) CHR28OH, C(O) CHR28ORZ6, C(=0) CHR28OC (=O) R27 or Rlo and R25 taken together may be =C(R28)2, that is, an optionally alkyl substituted methylene group; wherein, R26 is C1-C6 (alkyl, branched alkyl, cycloalkyl, haloalkyl, aralkyl, aryl; R27 is R26 or OR26; R28 is H, C1-C6 (alkyl, branched alkyl, cycloalkyl); excepted from the compounds of Structure [A] are the compounds, wherein R23 is OH, OC (=0) Rll, OP (O) (OH) 2, or OC(=O)(CH2)tCOOH; also excepted from the compounds of Structure [A] are the compound 3,11(3,17a,21-tetrahydroxy-5-pregnane-20-one (the 3-(x, 5-(3; 3-a, 5-a; 3-(3, 5-a; and 3-P, 5-(3 isomers of tetrahydrocortisol) , wherein Rls is =0, Rlo is a-OH, Rl is (3-CH3, R3 is (3-OH, R2 is H, R4 is H, R13 is a- or (3-OH, R14 is H, R12 is a- or P-H, R5 is H, R6 is H, R9 is H, R24 is C, and R23 is OH; for preventing or treating neovascularization.

According to yet a further aspect of the present invention, there is provided use of a therapeutically effective amount of a composition comprising an ophthalmically acceptable excipient and a compound of the formula:
Rl R25 R3 12 , R10 R4Rl 9 14 15 ~
~
Ri 3 4 6 R6 Structure [A]

4e Rl R25 R3 Rlo Rg O a~2 Rl 3 R6 Structure [B]

wherein Rl is H, (3-CH3 or (3-C2H5i R2 is F, Cy-C11 double bond, C9-C11 epoxy, H or Cl; R3 is H, OR26, OC (=O) R2-,, halogen, C9-Cll double bond, C9-C11 epoxy, =0, -OH, -0- alkyl (C1-C12) , -OC (=0) alkyl (C1-C12) ,-OC (=O) N(R) 2 or -OC (=0) OR7, and R is hydrogen, alkyl (C1-C4), or phenyl and each R is the same or different, and R7 is alkyl (C1-C12) ; R4 is H, CH3, Cl or F; R5 is H, OH, F, Cl, Br, CH3, phenyl, vinyl or allyl; R6 is H or CH3;
R9 is CH2CH2OR26, CH2CH2OC (=O) R27, H, OH, CH3, F, =CH2, CH2C (=O) OR2S, OR26, O(C=O) R2'7 or O(C=O) CH2 (C=O) OR26i Rlo is -C=CH, -CH=CH2, halogen, CN, N3, OR26, OC (=0) R27, H, OH, CH3 or Rlo forms a second bond between positions C-16 and C-17; R12 is H or forms a double bond with Rl or R14; R13 is halogen, OR26, OC (=0) R27, NH2, NHR26, NHC (=O) R27, N(R26)2, NC (=0) R27, N3, H, -OH, =0, -O-P (=O) (OH) 2, or -O-C (=0) -(CHz) tCOOH where t is an integer from 2 to 6; R14 is H or forms a double bond with R12; Rls is H, =0 or -OH; R23 is -OH, O-C (=O) -Rll, -OP (O) - (OH) 2, -0-C (=O) - (CH2) tCOOH
or R23 with Rlo forms a cyclic phosphate wherein t is an integer from 2 to 6; and Rll is -Y- (CH2) n-X- (CHZ) n,-SO3H, -Y' -(CH2)P-X' -(CH2) q-NR16R17 or -Z (CH2) rQ, wherein, Y is a bond or -0-; Y' is a bond, -0-, or -S-; each of X and X' is a bond, -CON (R18) -, -N (R18) CO-, -0-, -S-, -S (0) -, or -S (02) -; R18 is hydrogen or alkyl (C1-C4) ; each of R16 and R17 is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl; n is an integer of from 4 to 9; m is an integer of from 1 to 5; p is an integer of from 2 to 9; q is an integer of from 1 to 5; Z is a bond or -0-; r is an integer of from 2 4f to 9; and Q is one of the following: (1) -R19-CH2COOH, wherein R19 is -S-, -S (0) -, -S (O) 2-, -SO2N(R20) -, or N(R20) SO2-; and R20 is hydrogen or lower alkyl-(C1-C4); with the proviso that the total number of carbon atoms is R20 and (CHz)r is not greater than 10; or (2) -CO-COOH; or (3) CON(R21)CH(R22)COOH, wherein R21 is H and R22 is H, CH3, -CH2COOH, -CH2CH2COOH, -CH2OH, -CH2SH, -CH2CH2SCH3, or -CH2Ph-OH, wherein Ph-OH is p-hydroxyphenyl; or R21 is CH3 and R22 is H; or -N (R21) CH (R22) COOH is -NHCH2CONHCH2COOH; and pharmaceutically acceptable salts thereof; with the proviso that if R23 is a phosphate, it must form a cyclic phosphate, with Rlo when R13 is =0, except for the compound, wherein Rl is (3-CH3, R2 and R3 taken together form a double bond between positions 9 and 11, R4 and R6 are hydrogen, R12 and R14 taken together form a double bond between positions 4 and 5, R5 is a-F, R, is (3-CH3, Rlo is a-OH, R13 and Rls are =0 and R23 is -OP (O) -(OH) z, R24 is C or 0, and there may be a double bond between positions 1 and 2 when R24 is C; R25 is C(R15) CHz-R23, OH, OR26, OC (=0) R27, R26, COOH, C(=0) OR26, CHOHCH2OH, CHOHCH2OR26, CHOHCH2OC (=0) R27, CH2CH2OH, CH2CH2OR26, CH2CH2OC (=0) R27, CH2CN, CH2N3, CH2NH2, CH2NHR26, CH2N ( R26 ) 2, CH2OH , CH2OR26 , CHZO (C=0) R27, CH2O (P=O) (OH) 2, CH2O (P=0) (OR26) z, CH2SH, CH2S-R26, CH2SC (=O) R27, CHzNC (O) Rz7, C(O) CHR280H, C(O) CHR280R26, C(=O) CHR28OC (=O) R27 or Rlo and R25 taken together is =C (R28) 2, that is, an optionally alkyl substituted methylene group; wherein, R26 is C1-C6 (alkyl, branched alkyl, cycloalkyl, haloalkyl, aralkyl, aryl; R27 is R26 or OR26; R28 is H, C1-C6 (alkyl, branched alkyl, cycloalkyl); excepted from the compounds of Structure A
are the compounds, wherein R23 is OH, OC (=0) Rll, OP(O) (OH) 2, or OC(=O)(CH2)tCOOH; also excepted from the compounds of Structure A are the compound 3,11(3,17a,21-tetrahydroxy-5-pregnane-20-one (the 3-(x, 5-(3; 3-a, 5-a; 3-P, 5-a; and 3-(3, 5-P isomers of tetrahydrocortisol) , wherein R15 is =0, Rlo is a-OH, Rl is (3-CH3, R3 is P-OH, R2 is H, R4 is H, R13 is a- or (3-OH, R14 is H, R12 is 4g a- or (3-H, R5 is H, R6 is H, R9 is H, R24 is C, and R23 is OH; for preventing or treating ocular neovascularization.

According to still a further aspect of the present invention, there is provided use of a therapeutically effective amount of a composition comprising an ophthalmically acceptable excipient and a compound selected from the group consisting of:
21-nor-5(3-pregnan-3a,17a,20-triol-3-acetate; 21-nor-5a-pregnan-3a,17a,20-triol-3-phosphate; 21-nor-5(3-pregn-17(20)en-3a, 16-diol; 21nor-5(3-pregnan-3a, 17(3,20-triol; 20-acetamide-21-nor-5(3-pregnan-3a,17a-diol-3-acetate; 3(3-acetamido-5(3-pregnan-11(3,17a,21-triol-20-one-21-acetate; 21-nor-5a-pregnan-3a,17(3,20-triol; 21a-methyl-5(3-pregnan-3a,ll(3,17a,21-tetrol-20-one-21-methyl ether; 20-azido-21-nor-5(3-pregnan-3a,17a-diol;
20(carbethoxymethyl)thio-21-nor-5(3-pregnan-3a,17a-diol; 20-(4-fluorophenyl)thio-21-nor-5(3-pregnan-3a,17a-diol; 16a-(2-hydroxyethyl)-17(3-methyl-5(3-androstan-3a,17a-diol; 20-cyano-21-nor-5(3-pregnan-3a,17a-diol; 17a-methyl-5(3-androstan-3a,17p-diol; 21-nor-5(3-pregn-17 (20) en-3a-ol; 21-or-5(3-pregn-17 (20) en-3a-ol-3-acetate; 21-nor-5-pregn-17(20)-en-3a-ol-16-acetic acid 3-acetate; 3(3-azido-5(3-pregnan-ll(3,17a,21-triol-20-one-21-acetate; and 5(3-pregnan-11p,17a,21-triol-20-one; 4-androsten-3-one-17(3-carboxylic acid; 17a-ethynyl-5(10)-estren-17(3-ol-3-one;
and 17a-ethynyl-1,3,5(10)-estratrien-3,17(3-diol, for preventing or treating ocular neovascularization.

According to another aspect of the present invention, there is provided use of a pharmaceutically effective amount of a compound selected from the group consisting of: 21-methyl-50-pregnan-3cx, ll,6, 17cx, 21-tetrol-20-one-21-methyl ether; 30-azido-50-pregnan-ll,6,17a,21-triol-20-one-21-acetate; 3,6-acetamido-5,6-pregnan-11,(3,17a,21-triol-20-one-2l-acetate; 20-(4-4h fluorophenyl)thio-21-nor-50-pregnan-3a,17a-diol; 20-azido-21-nor-50-pregnan-3a,17a-diol; 20-(carbethoxymethyl)thio-21-nor-50-pregnan-3a,17a-diol; 20-acetamido-21-nor-5a-pregnan-3a,17a-diol-3-acetate; 16a-(2-hydroxyethyl)-170-methyl-5a-androstan-3u,17a-diol; 20-cyano-21-nor-50-pregnan-3a,17a-diol; 17a-methyl-50-androstan-3a,170-diol; 21-nor-50-pregnan-17(20)-en-3a-ol; 21-nor-50-pregnan-17(20)-en-3a-ol-3-acetate; 21-nor-50-pregnan-17(20)-en-3a-o1-16-acetic acid-3-acetate; 21-nor-50-pregnan-3a,17a,20-triol; 21-nor-50-pregnan-3a,17a,20-triol-3-acetate; 21-nor-50-pregnan-17(20)-en-3a,16-diol-3-acetate-16-(0-methyl) malonate; 21-nor-5u-pregnan-3a,17a,20-triol-3-phosphate; 21-nor-50-pregnan-17(20)-en-3a,16-diol; 21-nor-50-pregnan-3a,170,20-triol; 21-nor-5a-pregnan-3a,170,20-triol; 4-androsten-3-one-170-carboxylic acid; 17a-ethynyl-5(10)-estren-170-o1-3-one; 17a-ethynyl-1,3,5(10)-estratrien-3,170-diol; and 4,9(11)-pregnadien-17a,21-diol-3,20-dione-21-acetate, for controlling ocular hypertension.

According to yet another aspect of the present invention, there is provided a composition for controlling ocular hypertension comprising an ophthalmically acceptable excipient and a pharmaceutically effective amount of a compound selected from the group consisting of: 21-methyl-50-pregnan-3u,110,17a,21-tetrol-20-one-21-methyl ether; 30-azido-5g-pregnan-lla,l7u,21-triol-20-one-21-acetate; 30-acetamido-50-pregnan-110,17a,21-triol-20-one-21-acetate; 20-(4-fluorophenyl)thio-2l-nor-5a-pregnan-3a,l7a-diol; 20-azido-21-nor-50-pregnan-3u,17a-diol; 20-(carbethoxymethyl)thio-21-nor-50-pregnan-3u,17a-diol; 20-acetamido-2l-nor-50-pregnan-3a,17a-diol-3-acetate; 16a-(2-hydroxyethyl)-17a-methyl-50-androstan-3a,17a-diol; 20-cyano-21-nor-50-pregnan-3u,17a-diol; 17a-methyl-50-androstan-3u,170-diol; 21-nor-5Q-pregnan-17(20)-en-3a-ol; 21-nor-50-pregnan-17(20)-en-3u-ol-3-acetate; 21-nor-50-pregnan-17(20)-en-3a-ol-l6-acetic acid-3-acetate; 21-nor-50-4i pregnan-3a,17a,20-triol; 21-nor-5a-pregnan-3a,17a,20-triol-3-acetate; 21-nor-50-pregnan-17(20)-en-3a,16-diol-3-acetate-16-(0-methyl) malonate; 21-nor-5a-pregnan-3a,17a,20-triol-3-phosphate; 21-nor-5a-pregnan-17(20)-en-3a,16-dio1; 21-nor-5g-pregnan-3a,170,20-triol; 21-nor-5a-pregnan-3a,170,20-triol; 4-androsten-3-one-17R-carboxylic acid; 17a-ethynyl-5(10)-estren-17a-ol-3-one; 17a-ethynyl-1,3,5(10)-estratrien-3,170-diol; and 4,9(11)-pregnadien-17u,21-dio1-3,20-dione-2l-acetate.

According to another aspect of the present invention, there is provided a pharmaceutical composition useful in the treatment of ophthalmic inflammation, comprising: an ophthalmically acceptable excipient, an antiinflammatory effective amount of a glucocorticoid and an intraocular pressure controlling amount of an angiostatic steroid selected from the group consisting of: 21-Nor-5R-pregnan-3a,17a,20-triol-3-acetate; 21-Nor-5a-pregnan-3a,17a,20-triol-3-phosphate;
21-Nor-5R-pregn-17(20)en-3a,16-diol; 21-Nor-5R-pregnan-3a,17R,20-triol; 20-Acetamide-21-nor-50-pregnan-3a,17a-diol-3-acetate; 3R-Acetamido-5R-pregnan-11R,17a,21-triol-20-one-21-acetate; 21-Nor-Sa-pregnan-3a,17R,20-triol; 21a-Methyl-SR-pregnan-3a,l1R,17a,21-tetrol-20-one-2l-methyl ether; 20-Azido-21-nor-5R-pregnan-3a,17a-diol; 20(Carbethoxymethyl)thio-21-nor-5R-pregnan-3a,17a-diol; 20-(4-Fluorophenyl)thio-2l-nor-5R-pregnan-3a,17a-diol; 16a-(2-Hydroxyethyl)-17R-methyl-5R-androstan-3a,17a-diol; 20-Cyano-21-nor-5R-pregnan-3a,17a-diol;
17a-Methyl-5R-androstan-3a,17R-diol; 21-Nor-50-pregn-17(20)en-3a-oL; 21-Nor-50-pregn-17(20)en-3a-ol-3-acetate; 21-Nor-50-pregn-17(20)-3en-3a-ol-16-acetic acid 3-acetate; 3R-Azido-5R-pregnan-11R,17a,21-triol-20-one-21-acetate; 4,9(11)-Pregnadien-17a,21-diol-3,20-dione; 4,9(11)-Pregnadien-17a,21-diol-3,20-dione-21-acetate; 4-Androsten-3-one-17R-carboxylic acid; 17a-4j Ethynyl-5(10)-estren-17R-o1-3-one; 17a-Ethynyl-1,3,5(10)-estratrien-3,17R-diol; and 17a-Hydroxyprogesterone.

Brief Description of the Drawing Figure 1 compares the ability of angiostatic steroids to inhibit neovascularization in the rabbit cornea.

Detailed Description of Preferred Embodiments The development of blood vessels for the purpose of sustaining viable tissue is known as angiogenesis or neovascularization. Agents which inhibit neovascularization are known by a variety of terms such as angiostatic, angiolytic or angiotropic agents. For purposes of this specification, the ~> W 931]0]4l JPC'1'/US92/10133 term "angiostatic agent" means compounds which can be used to control, prevent, or inhibit angiogenesis.
The angiostatic agents of the present invention are steroids or steroid metabolites. For purposes herein, the term "angiostatic steroids" means 5 steroids and steroid metabolites which inhibit angiogenesis.

There is currently no effective method for controlling the neovascularization in angiogenesis-dependent diseases. In particular, ocular neovascularization has not been successfully treated in the past.
Neovascularization of tissues in the front of the eye (i.e. the cornea, iris, and the trabecular meshwork) and other conditions, including conditions in the back of the eye, for example, retinal, subretinal, macular, and optical nerve head neovascuiarization, can be prevented and treated by administration of the steroids of this invention. The angiostatic steroids'of the present invention are useful in preventing and treating neovascularization, including providing for the regression of neovascularization.

The angiostatic steroids can also be used for the control of ocular hypertension. In particular, the agents can be used for the treatment of primary open angle glaucoma.

The angiostatic steroids of the present invention have the following formula: R' ?.~ ~ R~
R3 R~ R3 ~ ~

**.. Ri Rg R
9 ~ g R13 Ria Re Re 14 5 %
Structure [A] Structure[B]
SUBSTITUTE SHEET

W093/10141 PCTlUS92/1013 3,~

wherein Rl is H, P-CH3 or P-C2Hs;
R2 is F, C9-C11 double bond, Cg-C11 epoxy, H or C1;
R3 is H, R26, OC(=0)R27, halogen, C9-C11 double bond, C9-C11 epoxy, =0, -OH, -a1ky1(C1-C12), - C(=0)alkyl(C1-C12), -OC(=O)ARYL, -OC(=O)N(R)2 or -OC(=0)OR7, wherein ARYL is furyl, thienyl, pyrrolyl, or pyridyl and each of said moieties is optionally substituted with one or two (C1-C4)alkyl groups, or ARYL is -(CH2)f-pheny1 wherein f is 0 to 2 and the phenyl ring is optionally substituted with I to 3 groups selected from chlorine, fluorine, bromine, alkyl(C1-C3), alkoxy(C1-C3), thioalkoxy-(C1-C3), C13C-, F3C-, -NH2 and -NHCOCH3 and R is hydrogen, alkyl (C1-Ca)1 or phenyl and each R can be the same or different, and R7 is ARYL as herein defined, or a1ky1(C1-C12);
R4 is H, CH3, C1 or F;
R5 is H, OH, F, Cl, Br, CH31 phenyl, vinyl or allyl;
R6 is H or CH3;
R 9 is CHZCH2OR26, CH2CH2OC (=0) R27, H, OH, CH3, F, =CH2, CI-12C (=0)0R28, , OR26, o(C= )R27 or o(C=o)CH2(C=o)oR26 Rla is -C-CH, -CH=CHz, halogen, CN, N31 OR26, OC(=0)R27, H, OH, CH3 or Rlo forms a second bond between positions C-16 and C-17;
R12 is H or forms a double bond with R1 or R14;
R13 is halogen, OR26, OC (=0) R27, NH2, NHR26, NHC (=0) Rz?, N( RZ6) Z, NC (=0 ) R27, N31 H, -OH, =0, -O-P(=0)(ON)21 or -0-C(=0)-(CH2)tC OH where t is an integer from 2 to 6;
R14 is H or forms a double bond with R12;
R15 is H, =0 or -OH;
and R23 with RIp forms a cycl i c phpsphate; -wherein R. and R15 have the meaning defined above;
or wherein R23 is -OH, 0-C(=0)-R11, - P(0)-(OH)2, or -O-C(-0)-(CH2)tC00H
wherein t is an integer from 2 to 6; and Rii i s-Y- (CH2)n-X- (CH2)m-S03H, _Y' (CH2)p-X' - (CFi2)q-NR16R 17 or -Z (CHZ)rR>
wherein Y is a bond or -0-; Y' is a bond, -0-, or -S-; each of X and X' is a bond;1C0N(R1s)-, -Ei(Ria)C -, -0-, -S-, -S(0)-, or -S(02)-; R18 is hydrogen or al kyl (C1-C4) ; each of Rls. arod R17 is a lower al kyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl or R16 and R17 taken together with the nitrogen atom to which each is attached forms a monocyclic heteracycle selected from pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or N(lower)alkyl-piperazino wherein alkyl has from 1 to 4 carbon atoms; n is an integer of from 4 to 9; m is an integer of from I to 5; p is 2 1~3 Li 0 :.3 WO 93/10141 PC r1US92l10133 an integer of from 2 to 9; q is an integer of from 1 to 5;
Z is a bond or -0-; r is an integer of from 2 to 9; and Q is one o-F the following:
(1) -R19-CH2C00H wherein R19 is -S-, -S(0)-, -S(0)2-, -SO2N(R20)-, or N(R20)S02-; and R 20 is hydrogen or lower alkyl-(C1-C4); with the proviso that the total number of carbon atoms in R20 and (CHz)r is not greater than 10; or (2) -CO-COOH; or (3) CON(RZ1)CH(RZZ)COOH wherein R 21 is H and RZZ is H, CH31 -CH2COOH, -CH2CH2COOH, -CHZOH, -CH2SH, -CH2CH2SCH3, or -CH2Ph-OH wherein Ph-OH is p-hydroxyphenyl;
or R21 i s CH3 and R22 is H;
or R21 and R22 taken together are -CH2CH2CH2-;
or -N(R21)CH(R22)COOH taken together is -NHCH2CONHCH2COOH; and pharmaceutically acceptable salts thereof;
Zs with the proviso that except for the compound wherein R1 is ,8-CH3, R2 and taken together form a double bond between positions 9 and 11, R4 and'R6 are hydrogen, R12 and R14 taken together form a double bond between pos i t i ons 4 and 5, R5 is -F, R9 is P-CH3, Rza is cc-OH, Rz3 and Rls are =0 and R 23 is -0P(0)-(OH)2, R13 is =0 only when R23 with Rlo forms the above described cyclic phosphate.
R24 = C, C1-C2 double bond, 0;
R 25 = C(Rls)CH2-R23, OH, ORzfi, QC(=0)R27, R26, COOH, C(=0)OR2fi, CHOHCH2OH, CHOHCH2OR26, CHOHCH2OC(=0)R27, CHZCH2 H, CH2CH2 R26, CHZCH2OC (= ) RZ7, CHZCN, CH2N3, CHZNHZ, CH2NHR26, CH2 N(R26)2, CH2OH, CH2 0R2s, CH2O(C=0)R27, CH2O(P=0) (OH)2, CH2O ( P=0) ( Rz6) 2, CHZSH, CH2S-Ra61 CH2SC (= ) Rz7, CH2NC(=0)R27õ C(= )CHR2$OH, C(=0)CHR28 R26, C(=0)CHRzaOC(= )R27 or RiQ
and R25 taken together may be =C(R28)2, that is, an optionally alkyl substituted methylene group;
wherein R26 = C, - C6 ( al kyl , branched al kyl , cycl oal kyl , hal oal kyl , aral kyl , aryl );" R27 = R26 + OR2E; R28 = H, C1-C6 ( al kyl , branched al kyl , cycl oa] kyl ).
Excepted from the compounds of Structure [A] are the compounds wherein R1 is P-CH3 or fi-C2H5;
R2 is HorCl;
as R3 is H, -0, -OH, -0-alkyl (C1-C12), -0C(=0)alkyl (C1-C1,), -OC(=O)ARYL, -OC(=0)N(R)2 or -0C(=. )OR7, wherein ARYL is furyl, thienyl, pyrrolyl, or WO 93/10141 1'Cr/tJS92/101?3 pyridyl and each of said moieties is optionally substituted with one or two (C1-C4)al ky1 groups, or ARYL i s-(CHZ)f-phenyl wherein f is 0 to 2 and the phenyl ring is optionally substituted with 1 to 3 groups selected from chlorine, fluorine, bromine, alkyl(C1-C3), alkoxy(Cl-C3), thioalkoxy-(C1-C3), C13C-, F3C-, -NH2 and -NHCOCH3 and R is hydrogen, alkyl (Ci-C4), or phenyl and each R can be the same or different, and R7 is ARYL as herein defined, or al kyl (C1-C22);
or wherein R2 and R3 taken together are oxygen (-0-) bridging positions C-9 and C-11; or wherein RZ and R3 taken together form a double bond between positions C-9 and C-11;
or R2 is -F and R3 is R-OH;
or R2 is -C1 and R3 is fl-C1;
i5 and R4 is H, CH31 Cl or F;
Rs is H, OH, F, C1, Br, CH31 phenyl, vinyl or allyl;
R6 i s H or CH3;
R9 is H, OH, CH3, F or =CH2;
Rlo is H, OH, CH3 or Rlo forms a second bond between positions C-16 and C-17;
R12 i s-H or forms a double bond with RA;
R13 is H, -OH, =0, -0-P(O)(OH)2, or -O-C(= )-(CH2)tCOOH where t is an integer from 2 'to 6;
R14 is H or forms a double bond with R12;
Ris is =0 or - H;
and R23 with R10 forms a cycl i c phosphate;
wherein R. and R15 have the meaning defined above;
or wherein R23 is -OH, -Q(=O)-R1l, -OP(0)-(OH)2, or - -C(=0)-(CH2)tC H
wherein t is an integer from 2 to 6; and Rll is -Y-(CH2)R-X-(CH2)m-S03H, -Y'-(CN2)p"X'-(CH2)q-NR16R17 or -Z(CH2),,Q, wherein Y is a bond or -0-; Y' is a bond, -0-, or -S-; each of X and X' is a bond,-CON(R18)-, -N(R18)CO-, -0-, -S-,-S(O)~-, or -S(02),-, R18 is hydrogen or alkyl (Cl-C4) ; each of R16 and R17 is a lower alkyl group of from 1 to 4 carbon atoms optionally substituted with one hydroxyl or Rls and R17 taken together with the nitrogen atom to which each is attached forms a monocyclic heterocycle selected from pyrrolidino, piperidino,.morpholino, thiomorpholino, piperazinoor N(lower)alkyl-piperazino wherein alkyl has from l to 4 carbon atoms; n is an integer of from 4 to 9;
m is an integer of from 1 to 5; p is an integer of from 2 to 9; q is an -= -.W 93/10141 ~ ~ ~ ~ 405 PC1'/L1S92/10133 integer o-F from I to 5;
Z is a bond or -0-; r is an integer of from 2 to 9; and Q is one of the following:
(1) -R19-CH2 COOH wherein R,9 is -S-, -S(0)-, -S(0)2-, -S02N(R20)-, or N( R2D)S02-; and R20 is hydrogen or lower al kyl -( C1-Ca) ; with the proviso that the total number of carbon atoms in R2Q and (CH2)r is not greater than 10; or (2) -CO-COOH; or (3) CON(R21)CH(R22)COOH wherein R21 is H and R22 is H, CH31 -CH2COOH, -CHzCHZC00H, -CHZOH, -CHZSH, -CHzCHzSCH3, or -CNZPh-OH wherein Ph-OH is p-hydroxyphenyl;
or R21 i s CH3 and R22 i s H;
or R21 and R22 taken together are -CH2CH2CH2-;
or -N(R21)CH(R2z)COOH taken together is -NHCH2CONHCH2C OH; and pharmaceutically acceptable salts thereof;
i.s with the proviso that except for the compound wherein R1 is fi-CH3, R2 and taken together form a double bond between positions 9 and 11, R4 and R6 are hydrogen, R12 and R14 taken together form a double bond between positions 4 and 5, R. i s -F, R9 i sfi-CH3, Rla i s -OH, R13 and R15 are =0 and R 23 i s-OP(0) -(OH)2, R13 i s =0 only when R23 with R10 forms the above described cycl i c za phosphate.

Unless specified otherwise, all substituent groups attached to the cyclopentanophenanthrene moiety of Structures [A] and [B] may be in either the alpha or beta pusition. Additionally, the above structures include a1a pharmaceutically acceptable salts of the angiostatic steroids.

~; , , , WO 93/ l 0141 lPCl['/ US?2/ 10l Preferred= angiostatic steroids' for the treatment of ocular hypertension, neovascular diseases and ocular inflammation are:

o-o O
d 11; OH r "'1rOH

HO''' N =N+=N
H H
21-METHYL-5p-PREGNAN-3oc,11p,17o , 3fi-AZIDO-5p-PREGNAN-21-TETROL-20- NE 21-METHYL ETHER 11p,17 ,21-TRTOL-20-ONE-21-ACETATE

OH

o O
Ho ~ .

H H H

3fi-ACETAMIDQ-5fi- 5#-PREGNAN-11p,17 ,21-TRI0L-20-0NE
PREGNANa11P,17 , 21-TRIOL-s C F
OH

H
20-(4-ELUOR PHEIdYL)THI0-21-NOR-5P-PREGNAN-3 ,17 -DIOL

'VVO 93/10141 PC'I'/1US92/10133 ii2123405 _ N=N+MH
,tittOH ' toililOH
HO
H Hp"
H
20-AZIDO-21-NOR-50-PREGNAN-3cx, 20-(CARBETHOXYMETHYL)THIO-21-NOR-50-17ot-DI L PREGNAN-3 ,17a-DIOL

iniOH
fillOH
OH
HO "", O Q H
H

20-ACETAMIDO-21-NOR-50-PREGNAN-3 , 16 -(2-HYDROXYETHYL)-17A-METHYL-17a-DI L-3-ACETATE 50-ANDR STAN-3 ,17 -DIOL
co N

õttoOH
HO

20-CYAN0-21-NOR-5fi-PREGNAN-3 ,1,7tx-DIOL

WO 93/10141 PC'I'/tJ592/10133 OH

HO HO
H H
17 -METHYL-5{3-ANDR05TAN- 21-NOR-5fi-PREGN-17(20)-EN-3-x-OL
3 ,17fi-DIOL

HO
-O
O~
a -:~---,o O
H H
21-NOR-5p-PREGN-17(20)-EN- 21-NOR-5p-PREGN-17(20)-EN-3 -0c-OH OH
'4 OH t,l%OH
, _ .

~, c HO ~~ H a H

~ 21-NOR-50 .PREGNAN-3oc,17 ,20-TRIOL 21-NOR-5P-PREONAN-17oc,20-DIOL-WO 93/10141 1'Ci/1JS92/10133 Q
Ohl 0 C) - - ~-I
q ~ ~~

0 ,, 4,9(11)-PREGNADIEN-17oc,21-DIOL-3,20- 4,9(11)-PREGNADIEN-17 ,21-DIONE-21-ACETATE DIOL-3,20-DIONE
m Ft o, - H t3 H
o- 0 H ON

OH Ot~
.
H ' HO dH
H

TETRAHYDROCORTEXOLONE (THS) TETRAHYDROCORTISOL (THF) WO 93/10141 PCI'IUS92/10133 OH
,1%1OH
.1110 O
~
Q )ry 0 0 0 H OI-! H
21-NOR-50-PREGN-17(20)-EN-3oc, 21-NOR-5oc-PREGNAN-3 ,17 ,20-TRI0L-16-DIOL-3-ACETATE-16-(0-METHYL)MALONATE 3-PHOSPNATE

OH

OH
1ir1OH

HO HO
H H
21-NOR-50-PREGN-17(20)-EN-3 ,16-DIOL 21-NOR-5fi-PREGNAN-3 ,17P,20-TRIOL

OH

OH
HO

21-NOR-5 -PREGNAN-3 ,17P,20-TRIOL ACID ROSTEN-3-ONE-17,6-CARBOXYLIC
~

f)H Ohl ~
~
~ ~~ ~~

17 -ETHYNYL-5(10)-ESTREN-I7fi-OL-3=0NE 17 -ETHYNYL-1,3,5(10)-ESTRATRIEN-3,17P-DIOL

2~~~~~~~
WO 93/ 10 14l PCF/ Ã1S92/ l 0133 Most preferred compounds for preventing and treating neovascularization are:
4,9(11)-Pregnadien-17 ,21-diol-3,20-dione-21-acetate 21-Nor-5p-pregn-17(20)-en-3 ,16-dio1-3-acetate-16-(0-s methyl)malonate 4,9(11)-Pregnadien-17 ,21-diol-3,20-dione 21-Nor-5p-pregnan-3 ,17ac,20-triol-3-acetate 21-Nor-5 -pregnan-3 ,17 ,20-triol-3-phosphate The angiostatic steroids of the present invention are useful in Yo inhibiting neovascularization and can be used in treating the neovascularization associated with: head trauma, spinal trauma, systemic or traumatic shock, stroke, hemorrhagic shock, cancer, arthritis, arteriosclerosis, angiofibroma, arteriovenous malformations, corneal graft neovascularization, delayed wound healing, diabetic retinopathy, granulations, 15 burns, hemangioma, hemophilic joints, hypertrophic scars, neovascular glaucoma, nonunion fractures, Osler-Weber Syndrome, psoriasis, pyogenic granuloma, retrolental fibroplasia, pterigium, scleroderma, trachoma, vascular adhesions, and solid tumor growth.

In particular, the angiostatic steroids are useful in preventing and treating any ocular neovascuiarization, including, but not limited to:
retinal diseases (diabetic retinopathy, chronic glaucoma, retinal detachment, sickle cell retinopathy, senile macular degeneration due to subretinal ne vascularization); rubeosis iritis; inflammatory diseases; chronic uveitis;
neoplasms (retinoblastoma, pseudoglioma); Fuchs' heterochromic iridocyclitis;
.25 neovascular glaucoma; corneal neovascularization (inflammator,y,.
transplantation, developmental hypoplasia of the iris); neovascularization resulting following a combined vitrectomy andlensectomy; vascuiar diseases.
(retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, carotid artery ischemia); pterigium; neova5cularization of the optic nerve;
ao and neovascularization due to penetration of the eye or contusive ocular injury.

2123405 - .
WO 93/10141 PC.'1'/US92/ 10133 The initiation of new blood vessel formation may arise quite differently in various tissues or as a result of different diseases. Many substances have been found to induce neovascularization, see, Folkman, et al., Angiogenic Factors, Science, Volume 235, pp. 442-447 (1987). However, it is believed, that once initiated, the process of neovascularization is similar in all tissues regardless of the associated disease, Furcht, Critical Factors Controlling Angfogenesis: Cell Products, Cell Matrix, and Growth Factors, Laboratory Investigation, Volume 55, No. 5, pp. 505-509 (1986).

There are a variety of theories regarding the mechanism of action o-f angiostatic steroids. For example, angiostatic steroid induced inhibition of neovascularization may occur due to, dissolution of the capillary basement membrane, Ingber, et al., Supra; inhibition of vascular endothelial cell proliferation, Cariou, et al., Inhibition of Human Endothelial Cel1 Proliferation by Heparin and Steroids, Cell Biology International Reports, is Vol. 12, No. 12, pp. 1037-1047 (December, 1988); effect on vascular endothelial cell laminin expression, Tokida, et al., Production of Two Variant Laminin Forms by Endotheliai Cells and Shift of Their Relative Levels by Angiostatic Steroids, The Journal of Biological Chemistry, Vol. 264, No. 30, pp. 18123-18129 (October 25, 1990); inhibition of vascular cell collagen synthesis, Maragoudakis, et al., Antiangiogenic Action of Heparin Plus Cortisone is Associated with Decreased Collagenous Protein,Synthesis in the Chick Chorioallantoic Membrane System, The Journal of Pharmacology and Experimental Therapeutics, Vol. 251, No. 2, pp. 679-682 (1989); and inhibitifln of vascular endothelial cell plasminogen activator activity, Ashino-Fuse, et al., Medroxyprogesterone Acetate, An Anti-Cancer and Anti-Angiogenic Steroid, Inhibits the Plasminogen Activator in Bovine Endothelial Cells, Int. J.
Cancer, 44, pp. 859-864 (1989).

There are many theories associated with the cause of neovascularization, and there may be different inducers depending on the disease or surgery involved, BenEzra, Neovasculogenic Ability of Prostaglandins, Growth Factors, and Synthetic Chemoattractants, American Journal of Ophthalmology, Volume 86, No. 4, pp. 455-461, (October, 1978). Regardless of the cause or the associated disease or surgery, it is believed that angiostatic agents work by inhibiting one or more steps in the process of neovascularization. Therefore, the angiostatic steroidsof this invention are useful in the treatment and prevention of neovascularization associated with a variety of diseases and surgical complications.

The angiostatic steroids of the present invention may be incorporated, together with an ophthalmically acceptable excipient, in various formulations for delivery. The type of formulation (topical or systemic) will depend on the site of disease and its severity. For administration to the eye, topical formulations can be used and can include ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, buffers, sodium chloride, and water to form aqueous sterile ophthalmic solutions and suspensions. In order to prepare sterile ophthalmic ointment formulations, an angiostatic steroid is combined with a preservative in an appropriate vehicle, such as mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations comprising the angiostatic steroids of the present invention can be prepared by suspending an angiostatic steroid in a hydrophilic base prepared from a combination of, for example, Carbopol (a carboxy vinyl polymer available from the BF

Goodrich Company) according to published formulations for analogous ophthalmic preparations. Preservatives and antimicrobial agents may also be incorporated in such gel formulations. Systemic formulations for treating ocular neovascularization can also be used, for example, orally ingested tablets and formulations for intraocular and periocular injection.

The specific type of formulation selected will depend on various factors, such. as the angiostatic steroid or its salt being used, the dosage frequency, and the location of the neovascularization being treated. Topical ophthalmic aqueous solutions, suspensions, ointments, and gels are the preferred dosage forms for the treatment of neovascularization in the front of the eye (the cornea, iris, trabecular meshwork); or 17a neovascularizatiori of the back of the eye if the angiostatic agent can be formulated such that it can be delivered topically and the agent is able to penetrate the tissues in the front of the eye. The angiostatic steroid will normally be contained in these formulations in an amount from about 0.01 to about 10.0 weight/percent. Preferable concentrations range from about 0.1 to about 5.0 weight/percent. Thus, for topical administration, these formulations: are delivered to the surf'ace of the eye one to six times a day, depending on the routine discretion of the skilled clinician. Systemic administration, for example, in the form of tablets is useful for the treatment of neovascularization. particularly of W093/lOl4l 212345~~~
PC'T/1U592/ l 0133 the back of the eye, for example, the retina. Tablets containing 10-1000 mg of angiostatic agent can be taken 2-3 times per day depending on the discretion of the skilled clinician.

The preferred compounds for controlling ocular hypertension are: 21-Nor-a#-pregnan-3 ,17 ,20-triol;5p-pregnan-11p,17 ,21-triol-20-one;4,9(11)-Pregnadien-17 ,21-diol-3,20-dione-21-acetate, and 4,9(11)-Pregnadien-170C,21-dio1-3,20-dione. The most preferred compound is 4,9(11)-Pregnadien-17a,21-diol-3,20-dione-21-acetate.

Without intending to be bound by any theory, it is believed that the angiostatic steroids of the type described above act to control intraocular pressure by inhibiting the accumulation or stimulating the dissolution of amorphous extracellular material in the trabecular meshwork of the eye. The presence of this amorphous extracellular material alters the integrity of the healthy trabecular meshwork and is a symptom associated with primary open angle glaucoma (POAG). It is not well understood why this amorphous extracellular material builds up in the trabecular meshwork of persons suffering from POAG. However, it has been found that the amorphous extrace11u1ar material is generally composed of glycosaminoglycans (GAGs) and basement membrane material; see, Ophtha7mo7ogy, Vol.90, No.7 (July 1983); Mayo C7in. Proc, Vo1.61,-ppo59-67 (Jan.1986)y and Pediat. Neurosci,. Vo1.12, pp.240-251 (1985-86). When these materials build up in the trabecular meshwork, the aqueous humor, normally present in the anterior chamber of the eye, cannot leave this chamber through its normai route (the trabecular meshwork) at its normal rate. Therefore, a normal volume of aqueous humor is produced by the ci l i ary processes of the eye and introduced into the anterior chamber, but its exit through the trabecular meshwork is abnormally s]ow. This results in a buildup of pressure in the eye, ocular hypertension, which can translate into pressure on the optic nerve. The ocular hypertension so generated can lead to nl9ndness due.to damage to the optic ncrve.

Many methods for treating primary open angle glaucoma and ocular hypertension concentrate on blocking production of aqueous humor by the eye.
However, aqueous humor is the fundamental source of nourishment for the tissues of the eye, particularly the cornea and lens which are not sustained by blood suppiy. Therefore, it is not desirable to deprive these tissues of ,..._.. , _ ,.: . . ..
.. ,.., ;:..:....._ , .

the necessary irrigation and nutrition provided by the aqueous humor. It is desirable to strive for normal exit of the aqueous humor by maintaining the normal integrity of the trabecular meshwork. This is accomplished according to the present invention by the administration of angiostatic steroids.

It is believed that the angiostatic steroids disclosed herein function in the trabecular meshwork in a similar manner as shown by Ingber, et al., wherein it was shown that angiostatic steroids caused dissolution of the basement membrane scaffolding using a chick embryo neovascularization model;
E'ndocrino7oqy, 119, pp.1768-1775 (1986). It is believed that the angiostatic steroids of the present invention prevent the accumulation, or promote the dissolution of, amorphous extracellular materials in the trabecular meshwork by inhibiting the formation of basement membrane materials and glycosaminoglycans. Thus, by preventing the development of these materials or promoting their dissolution, the normal integrity of the trabecular meshwork is is retained and aqueous humor may flow through the trabecular meshwork at normal rates. As a result, the intraocular pressure of the eye is controlled.
The angiostatic steroids of the present invention may be incorporated in various formulations for delivery to the eye to control ocular hypertension. For example, topical formulations can be used and can include ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, buffers, sodium chloride and water to form aqueous sterile ophthalmic solutions and suspensions. In order to prepare sterile ophthalmic ointmen-t formulations, an angiostatic steroid is combined with a preservative in an appropriate vehicle, such as mineral oil, liquid lanolin or white petro7atum.
Sterile ophthalmic gel formulations comprising the angiostatic steroids of the present invention can be prepared by suspending an angiostatic steroid in a hydrophilic base prepared from a combination of, for examp'le, CarbopolO 940 (a carboxyvinyl polymer available from the B.F. Goodrich Company) according to , published formulations for analogous ophthalmic preparations.
Preservatives and tonicity agents may also be incorporated in such gel formulations. The specific type of formulations selected will depend on various factors, such as the angiostatic steroid or its salt being used, and the dosagefrequency. Topical ophthalm-ic aqueous solutions, suspensions, ointments and gels are the preferred dosage forms. The angiostatic steroid will normally be contained in these formulations in an amount of from about dVO 93/ 10141 ~~ 2 3 4 0~'~ ;=4 ~!~ ;' s PCT/US92/ 101,2.~

0.005 to about 5.0 weight percent (wt.%). Preferable concentrations range from about 0.05 to about 2.0 wt.%. Thus, for topical administration, these formulations are delivered to the surface of the eye one to four times per day, depending upon the routine discretion of the skilled clinician.

s In addition, antiinflammatory compositions of glucocorticoids can contain one or more angiostatic steroids of the present invention, preferably tetrahydrocortisol. These compositions will contain one or more glucocorticoids in an antiinflammatory effective amount and will contain one or more angiostatic steroids of the present invention in an amount effective io to inhibit the IOP elevating effect of the glucocorticoids. The amount of each component will depend on various factors, such as the relative tendency of certain glucocorticoids to cause IOP elevations, the severity and type of ocular inflammation being treated, the estimated duration of the treatment, and so on. In general, the ratio of the amount of glucocorticoid to the 15 amount of angiostatic steroid on a weight to weight basis will be in the range of 10:1 to 1:20. The concentration of the glucocorticoid component will typically be in the range of about 0.01% to about 2.0% by weight. The concentration of the angiostatic steroid component will typically be in the range of about 0.05% to about 5.0% by weight.

20 The above-described active ingredients may be incorporated into various types of systemic and ophthalmic formulations. For example, for topical ocular administration, the active ingredients may be combined . wi th ophthalmological1y acceptable preservatives, surf actants,vi scosi ty enhancers, buffers, toxicity agents and water to form an aqueous, sterile ophthalmic 5uspension. In order to prepare sterile ophthalmic ointment formulations, the active i ngredi ents are c mbi ned with a preservative in an appropriate vehi cl e, such as mineral oil, liquid lanolin, or white petrolatum. Sterile ophthalmic gel formulations may be prepared by suspending the active ingredient in a hydrophilic base prepared from the combination of CarbopolQ0 940 (acarboxy vinyl polymer available from the B.F. Goodrich Company) according to published formulationsfor analogous ophthalmic preparations; preservatives and tonicity agents can also be incarporated. The specific -type of formulation selected will depend on various factors, such as the severity and type of ophthalmic inflammation being treated, and dosage frequency. Ophthalmic solutions, suspensions, ointments and gels are the preferred dosage forms, and topical application to the inflamed ocular tissue is the preferred route of administration.

It is evident to be skilled in the art that the compounds and compositions of this inverition are generally sold in the form of cominercial packages comprising the compound or composition togethier with instructions for using them in treating or preventing the various conditions or diseases disclosed herein.

The following examples illustrate formulations and synthesis of compounds of the present invention, but are in no way limiting.

Example 1 The topical compositions are useful for controlling ocular hypertension or controlling ocular neovascularization.
Component wt.%

Angiostatic Steroid 0.005-5.0 Tyloxapol 0.01-0.05 HPMC 0.5 Benzalkonium Chloride 0.01 Sodium Chloride 0.8 Edetate Disodium 0.01 NaOH/HC1 q.s. pH 7.4 Purified Water q.s. 100 mL

21a Example 2 The composition is useful for controlling ocular hypertension.

Component wt.%
21-Nor-5p-pregnan-3a,17a,20-triol 1.0 Tyloxapol 0.01-0.05 HPMC 0.5 Banzalkonium Chloride 0.01 Sodium Chloride 0.8 Edetate Disodium 0.01 NaOH/HC1 q.s. pH 7.4 Purified Water q.s. 100 mL

WO 93/10141 2123405 PC"i'/ZJS92/10133 The above formu1ation is prepared by first placing a portion of the purified water into a beaker and heating to 90 C. The hydroxypropylmethylcellulose (HPMC) is then added to the heated water and mixed by means of vigorous vortex stirring until all of the HPMC is dispersed.
The resul ti ng mixture is then al l owed to cool whi 1 e undergoing mi xi ng -i n order to hydrate the HPMC. The resulting solution is then sterilized by means of autoclaving in a vessel having a liquid inlet and a hydrophobic, sterile air vent filter.

The sodium chloride and the edetate disodium are then add'ed to a second portion of the purified water and dissolved. The benzalkonium chloride is then added to the solution, and the pH of the solution is adjusted to 7.4 with O.1M NaOH/HC1. The solution is then sterilized by means of filtration.

21-Nor-5fi-pregnan-3a,17 ,20-triol is sterilized by either dry heat or ethylene oxide. If ethylene oxide sterilization is selected, aeration for at as least 72 hours at 50 C. is necessary. The sterilized steroid is weighed aseptically and placed into a pressurized balimill container. The tyloxapol, in sterilized aqueous solution form, is then added to the ballmill container.
Steri l i zed glass ba1 l s are then added to the container and the contents of the container are milled aseptically at 225 rpm for 16 hours, or until all particles are in the range of approximately 5 microns.

Under aseptic conditions, the micronized drug suspension formed by meags of the preceding step is=then poured into the HPMC solution with mixing. The ballmill container and balls contained therein are then rinsed with-a-portion of the solution containing the sodium chloride, the edetate disodium and 2s benzalkonium chloride. The rinse is then added aseptically to the HPMC
solution, The fi.,al volume of the solution is then adjusted with purified water and, if necessary, the pH of the solution is adjusted to pH 7.4 with NaOH/H~l.
,. , 212,3405 W093/10141 PCTl1J592/10133 Example 3 The following formulation is representative of the aritiinflammatory compositions of the present invention.

Comoonent WAA
4,9(11)Pregnadien-17oc,21-diol-3,20- 1.0 dione-21-acetate Dexamethasone 0.1 Tyloxapol 0.01 to 0.05 HPMC 0.5 Benzalkonium Chloride 0.01 Sodium Chloride 0.8 Edetate Disodium 0.01 MaOH/HCl q.s. pH 7.4 Purj f i ed Water q. s. 100 mL

The above formulation is prepared in the same manner set forth in Example 2, sterilizing and adding the dexamethasone to the steroid before piacing both into a pressurized ballmill container.

Exa e 4 The fol l owi ng for mul ati on is another example of the ant i i nf lammatory compositions of the present invention.

Tetrahydrocortisol 1.0 Prednisolone Acetate 1.0 Tyloxapol 0.01 to 0.05 HPMC 0.5 Benzalkonium Chloride 0.01 Sodium Chloride 0.8 Edetate Disodium 0.01 Na H/HC1 q.s. pH 7.4 PurifiedWater q.s. 100 mis 'VVO 93/90141 r~.~.~ ~ ~ PC T/1JS92/101~3 (~ 24 r ia~4.tJ-aTq"i~ prepared in the same manner set forth in The above fo~ ~.:
Example 2, sterilizing and adding the prednisolone acetate to the steroid before placing both into a pressurized ba11mii1 coritainer.

The following formulations are representative of compositions used for the treatment of angiogenesis dependent diseases.

ExamDle 5 FORMULATION FOR ORAL ADMINISTRATION
Tablet:
10-1000 mg of angiostatic steroid with inactive ingredients such 20 as starch, lactose and magnesium stearate can be formulated according to procedures known to those skilled in the art of tablet formulation.

Examp 6 FORMULATION FOR STERILE INTRAOCULAR INJECTION
is each mL contains: ~
Angiostatic Steroid 10-100 mg Sodium Chloride 7.14 mg Potassium Chloride 0.38 mg Calcium chloride dihydrate 0.154 mg 20 Magnesium chloride hexahydrate 0.2 mg Dried sodium phosphate 0.42 mg Sodium bicarbonate 2.1 mg Dextrose 0.92 mg Hydrochloric acid or sodium hydroxide 25 to adjust pH to approximately 7.2 Water for i njecti on WO 93/10141 2123105, PC'I'/1JS92/10133 amlpe7 FORMULATION FOR TOPICAL OCULAR SOLUTION
21-Nor-5 -pregnan-3 ,17 -20-triol 1.0%
-3-phosphate s Benzalkonium chloride 0.01%
HPMC 0.5%
Sodium chloride 0.8%
Sodium phosphate 0.28%
Edetate disodium 0.01%
io NaOH/HCl q.s. pH 7.2 Puri f i+ed Water q.s. 100 mL
ExaMD1g 8 FORMULATION FOR TOPICAL OCULAR SUSPENSION
innredient Emoutlt (wts%) is 4,9(11)-Pregnadien-17 ,21- 1.0 diol-3,20-dione-21-acetate Tyloxapol 0.01 to 0.05 w HPMC 0.5 Benzalkonium chloride 0.01 20 Sodium chloride -4.8 Edetate Disodium 0.01 NaOH/HC1 q.s. pH 7.4 Purified Water q.s. 100 mL

T'he formulation is prepared by first placing a portion of the purified 2s water into a beaker and heating to 90 C. The hydroxypropylmethylcellulose (HPMC) is then added to the heated water and mixed by means of vigorous vortex stirring until all of the HPMC is dispersed. The resulting mixture is then allowed to cool while undergoing mixing in order to hydrate the HPMC. The resul ti ng sol uti on is thlen steri l i zed by means of autocl avi ng in a vessel having a liquid inlet and ~a hydrophobic, sterile air vent filter.

-------------'7 y y The sodium chloride and the edetate disodium are then added to a second portion of the purified water and dissolved. The benzalkonium chloride is then added to the solution, and the pH of the solution is adjusted to 7.4 with 0.1M NaOH/HC1. The solution is then sterilized by means of filtration.

The 4,9(11)-Pregnadien-17a,21-dioi-3,20-dione-21-acetate is sterilized by either dry heat or ethylene oxide. If ethylene oxide sterilization is selected, aeration for at least 72 hours at 50 C is necessary. The sterilized 4,9(11)-Pregnadien-17a,21-diol-3,20-dione-21-acetate is weighed aseptically and placed into a pressurized ba11mi11 container. The tyloxapol, in io sterilized aqueous solution form, is then added to the ba11mi11 container.
Sterilized glass balls are then added to the container and the contents of the container are milled aseptically at 225 rpm for 16 hours, or until all particles are in the range of approximately 5 microns.

Under aseptic conditions, the micronized drug suspension formed by means of the preceding step is then poured into the HPMC solution with mixing. The bailmi7l container and balls contained therein are then rinsed with a portion of the solution containing the sodium chloride, the edetate disodium and benza7konium chloride. The rinse is then added aseptically to the HPMC
solution. The final volume of the solution is then adjusted with purified water and,.if necessary, the pH of the solution is adjusted to pH 7.4 with Na0N/HC1. The formulation will be given topically, in a therapeutically effective amount. In this instance, the phrase "therapeutically effective amount" means an amount' which is sufficient to substantially prevent or reverse any ocular neovascu1arization. The dosage regimen used will depend on the nature of the neovascui ari zat i on, as well as various other factors such asthe patient's age, sex, weight, and medical history.

fxa ple9 FORMULATION FOR ORAL ADMINISTRATI N
Tablet:

5-100 mg 21-Nor-5#-pregnan-3 -17 -20-triol with inactive ingredients such as starch, lactose and magnesium stearate can be formulated according to procedures known to those skilled in the art of tablet formuTation.

Example 10 Formulation for Sterile Intraocular Injection each mL
contains:

4,9(11)-Pregnadien-17a,21-diol-3,20-dione 10-100 mg Sodium Chloride 7.14 mg Potassium Chloride 0.38 mg Calcium chloride dihydrate 0.154 mg Magnesium chloride hexahydrate 0.2 mg Dried sodium phosphate 0.42 mg Sodium bicarbonate 2.1 mg Dextrose 0.92 mg Hydrochloric acid or sodium hydroxide to adjust pH to approximately 7.2 Water for injection Example 11 Inhibition of angiogenesis in the rabbit corneal neovascularization model:

The corneal pocket system of BenEzra (Am. J.
Ophthalmol 86:455-461, 1978) was used to induce corneal neovascularization in the rabbit. A small Elvax* pellet containing 0.5,ug of lipopolysaccharide (LPS) was inserted into the middle of the corneal stroma and positioned 2.5 mm from the limbus. An additional Elvax* pellet with or without 50,ug of angiostatic steroid was placed next to the LPS implant. The *Trade-mark 27a eyes were examined. daily and the area of neovascularization calculated. Results after 8 days of LPS implantation are shown in Figure 1. THF - tetrahydrocortisol; A = 4,9(11)-Pregnadien-17a,21-diol-3,20-d.ione-21-acetate; B = 4,9(11)-Pregnadien-17a,21-diol-3,20-d.ione. As can be seen, A & B totally inhibited corneal neovascularization, whereas THF partially inhibited the neovascular response.

WO 93/10141 F'CI'/US92/10133 ~M ,l~j= y,.i, .' =' ~'''"=.

Examp1e 12 Preparation of 5fi-Preqnan-11fi. 17 a 21-triol-20-one 7etrahydrocotiul-E-21-t-butvldiphenv~i1y1 et er (pS03842) A solution of 4.75 g (17.3 mmol) of t-butyldiphenylchlorosilane in 5 mL of dry DMF was added dropwise to a stirred solution of 5.7 g (15.6 mmol) of tetrahydrocortisol-F (Steraloids No. P9050) and 2.3 g(19 mmol) of 4-dimethylaminopyridine (DMAP) in 30 mL of dry DMF, under N2, at -25 to -30 C
(maintained with CO 2 - MeCN). After a further 20 min at -30 C, the mixture was allowed to warm to 23 C overnight.

The mixture was partitioned between ether and water, and the organic solution was washed with brine, dried (MgSOa)1 filtered and concentrated to give 10.7 g of a white foam.

This material was purified by flash column chromatography (400 g silica; 62.5 to 70% ether/hexane). 'The 3-siloxy isomer eluted first, followed by mixed is fractions, followed by the title compound. The concentrated mixed fractions (4.0 g) were chromatographed on the same column with 35% ethyl acetate/hexane.
The total yield of the 3-siloxy isomer was 0.42 g (5%), and of the title compound, 5.05 g(53.5%). Continued elution with 25% MeOH/EtOAc allowed recovery of unreacted tetrahydrocortisol-F.

NMR (200 MHz 'H) (CDC13)o 60.63 (s, 3H, Me-18); 1.11 (s, 9H, t-Bu); 1.12 (s, 3H, Me-19); 2.57 (t, J=13, 1H, H-8); 2.6 (s, 1H, OH-17); 3.63 (sept, J=2.5, IH, H-3); 4.15 (br s, IH, H-11); 4.37 and 4.75 (AB, J=20, 2H, H-21); 7.4 (m, 6H) and 7:7 (m, 4H) (Ph2), NMR (200 MHz 'H) (DMS -d6): 60.64 (s, 3H, Me-18); 1.02 (s, 9H, t-Bu); 1.07 (s, 3H, Me-19); 2.50 (t, J=13, 1H, H-8); 3:37 (m, 111, H-3); 3.94 (d, J=2, 1H, OH-11); 4.00 (br s, 1H, H-11); 4.42 (d, J=5, 1H, 0H-3); 4.38 and 4.83 (AB, J-20, 2H, H-21); 5.11 (s, 1H, H-17); 7.45 (m, 6H) and 7.6 (m, 4H) (Phz) NMR (50.3'- MHz 1sC) (CDC13): 7. (C-18); 19.3 (C-16); 23.7 (C-15); 26.3 (C-lVVO 93/10141 P('T/US92/10133 29 ' 7); 26,.6- (C-19); 26.8 (Me3C); 27.2 (C-6); 30.9 (C-2); 31_5 (C-8); 34.1 (Me3C);
34.8 (C-10); 35.2 (C-1); 36.2 (C-4); 39.7 (C-13); 43.5 (C-5); 44.3 (C-9); 47.4 (C-12); 52-d (C-14); 0.8 (C-11); 68.9 (C-21); 71.7 (C-3); 89.8 (C-14); 1L7.8, 12, 132.8, 132.9, .135.7, 135.8 (diastereotopic Ph2); 208.8 (C-20).
Underlined resonances showed inversion in the APT experiment. Assignments:
E. 8reitmaier, W. Voelter "Carbon-13 NMR Spectroscopy," 3d ed., VCH, 1987; pp.
345-348.

IR (KBr) 3460, 2930, 2860, 1720, 1428, 1136, 1113, 1070, 1039, 703 cm 1.
This compound did not show a sharp melting point but turned to a foam at 80-100 C. Numerous attempts at recrystallization failed.

5 -Prggnan-I18, 17 , 21-triot 20-one A solution of PS03842 (0.91 g, 1.50 mmol) and thiocarbonyl diimidazole (1.05 g, 5.9 mmol) in 8 mL of anhydrous dioxane was refluxed under N 2 for 3.5 h.
The cooled solution was partitioned between ether and water and the organic is solution was washed with brine, dried (MgSO4), filtered and concentrated.
The residue was chromatographed (120 g Si02, 35% EtOAc/hexane) giving 0.86 g (80%) of the imidazolyl thioester.

A solution of 0.75 g(1.05 mmol) of this compound in 100 mL of anhydrous dioxane was added dropwise over 2.2 h to a rapidly stirred, refluxing solutioyi of 1.6 mL (5.9 mmol) of Bu3 SnH in 100 mL of anhydrous dioxane under N2, After a further I h at reflux, the solution was cooled, concentrated and the residue chromatographed (200 g SiO2, 91% EtOAc/hexane) giving 0.43 g (70%) of the 3-deoxy-21-silyl ether. This material was dissolved in 20 mL of inethanol;
Bu4NF'3H20 (0.50 g, 1.6 mmol) was added, ancithe mixture was heated to reflux under N2 for 4 h. The cooled solution was diluted with 2 volumes of EtOAc, concentrated to 1/4,volume, partitioned (Et Ac/H2O), and the organic solution was washed with brine, dried (MgSO4), filtered and concentrated. The residue (0.40 g) 'was chromatographed (30 g Si02, 40% EtOAc/hexane) to give 0.25 g (98%) of an oil.

This oil was crystallized (n-BuCl) to afford 0.14 g of the title compound as a white solid, m.p. 167-170 C.

,;. _ .
WO 93/ 10141 PC'['/ LJS92/ 10133 IR (KBr): 3413 (br), 2934, 1714, 1455, 1389, 1095, 1035 cm-1.
MS (CI): 351 (M +1).

NMR (200 MHz 'H, DMSO-dE): 60.69 (s, 3H, Me-18); 1.14 (s, 3H, Me-19); 0.8-2.0 (m); 2.5 (t, J=13, 1H, H-8); 3.96 (d, J=2, 1H, OH-11); 4.1 (br s, 1H, H-s 11); 4.1 and 4.5 (AB, further split by 5 Hz, 2H, H-21); 4.6 (t, J=5, 1H, OH-21); 5.14 (s, 1H, OH-17).

~].. Calc'd for C21H3404: C, 71.96; H, 9.78.
Found: C, 71.69; H, 9.66.

Examale 13 10 Prgparation of ~I-Methvd-5B-preanari-3 : 1184 I7 , 21-tetroi -251-4oe ~l-Methyl ether Sodium hydride (60% oil dispersion, 0.10 g, 2.5 mmol) was added to a stirred solution of tetrahydrocortisol-F (0.73 g, 2.0 mmol) and CH31 (0.60 mL, 9.6 mmol) in 8 mL of anhydrous DMF under N2. Hydrogen was evolved, and the is temperature rose to 35 C. After 1 h, the mixture was diluted with EtOAc, extracted with water (until neutral) and brine, dried (MgSO4), filtered and concentrated. The residue was chromatographed (70 g Si02, 80% EtOAc/hexane) to give 0.17 g of a white solid, MS (CI) = 395 (M +1). This material w4s recrystallized (EtOAc-gt-BuC1) to afford 0.12 g(16I ) of the title compound as 20 a feathery white solid, m.p. 208-213 C. -IR (KRr): 3530, 3452, 2939, 2868, 1696 (s, CO), 1456, 1366, 1049 cm-1.

NMR (200 MHz H, DMS -d6): 60.74 (s, 3H, Me-18); 1.09 (s, 3H, Me-19); 1.14 (d, J=6.6,, 3H, C-21 Me); 0.8-2.0 (m); 2.47 (t, J=13, 1H, H-8); 3.18;(s, 3H, OMe); 3.35 (m, IH, Hp3);4:.00 (d, J=2, IH, OH-11); 4.07 (br s, 1H, H-11); 4.37 25 (q, J=6.6, 1H, H-21); 4.43 (d, J=5, 1H, OH-3); 5.16 (s, IH, OH-17).

Anil. Calc'd for C2aH3g05: C, 70.01; H, 9.71.
Found: C,70.06; H, 9.76.

W093/10141 . PCT/US92/10133 Examp1e 14 F~gr a~ation of 38-A,zi do-5fi-pregnan-I~,.
.17 a 21-'tri o1-0-one-2l-acetate A solution of triphenylphosphine (2.6 g, 10 mmol) in 10 mL of toluene was carefully added to a stirred solution of PS03842 (see Example 4) (1.75 g, 2.90 mmol), diphenylphosphoryl azide (2.2 mL, 10.2 mmol) and diethyl azodi carboxy1 ate (1. 55 mL, 10 mmol ) under Nz, keeping the internal temperature below 35 C (exothermic). The solution was stirred for 1.2 h, then diluted with ether, washed with water and brine, dried (MgSOQ), filtered and concentrated and the residue (9.5 g, oil) chromatographed 175 g SiO2, 15%
EtOAc/hexane) giving 1.83 g of a viscous oil.

A solution of 1.73 g of this material and 1.75 g(5.5 mmol) of BuaNP'3Hz0 in mL of methanol was refluxed under N2 for 2.5 h. The crude product (1.94 g) was isolated with ethyl acetate and chromatographed (100 g SiO2, 50%
15 EtOAc/hexane) giving 0.60 g (56%) of a white semisolid. Trituration (4:1 hexane-ether) gave 0.57 g(53la) of a solid.

A stirred solution of 0.40 g of this material in 3 mL of dry pyridine was treated with 0.3 mL of acetic anhydride and stirred overnight at 23 C under N2. The mixture was quenched with 1 mL of methanol, stirred for 15 min, 20 diluted with ether, washed with 1M aqueous HC1, water (until neutral), brinq, dried (MgSO4), filtea~ed,and c ncentrated. The residue (0.41 g, oil) was chromatographed (35 g Si02, 33% EtOAc/hexane) to afford 0.33 gP60) of the title compound as a white foam, m.p. 80-90 C (dec).

IR (KBr): 3505, 2927, 2866, 2103 (vs), 1721 (sh 1730), 1268, 1235 cm-1.

NMR (200 MHz 1H, CDC13): 50.92 (s, 3H, Me-18); 1.21 (s, 3H, Me-19); 1.0-2.1 (m)=, 2.17 (s, 3H, Ac); 2.25 (s 1H, 0N-17); 2.74 (m, 1H, H-8); 3.97 (br s, 1H, H-3); 4.31 (br s, IH, H-11); 4.94 (AB, d=17, Av-60, 2H, H-21), Ana].. Calc'd for C23H35N305; C, 63.72; H, 8,14; N, 9.69.
Found: C, 63.39; H, 8.18; N, 9,45.

~ ' /C= ,~ ,., W0 93/10141 PCfi'/iJS92/10133 r..,..=

Examole 15 Preparation of 3fi-Acetam1i do-5fi-pregnan_116, 1 7a- 1-triol-20-one-21 -acetate A solution of 3fi-azido-5fi-pregnan-11p,17 ,21-triol-20-one-21-acetate (0.15 g, 0.35 mmol) in 8 mL of absolute ethanol containing 0.03 g of 10% Pd on C was stirred under H2 ( 1 atm) at 23 C for 2 h. The mixture was fi 1 tered and concentrated, the residue dissolved in EtOAc, the basic material extracted into 1M aqueous HC1, liberated (Na2 CO3), extracted (EtOAc) and the organic extract washed with water (until neutral) and brine, dried (MgSO4)1 filtered and concentrated to provide 58 mg of a solid.

This material was acetylated (1.0 mL of dry pyridine, 0.20 mL of Ac20, 23 C, N2, overnight), followed by workup (as described for the steroid of Example 14 [last step]) affording a crude product that was chromatographed (25 g SiOz) EtOAc). This product was triturated with ether to afford 51 mg (33%) of is product as a white solid, m.p. 179-181 C.

MS (CI, isobutane): (M +1) = 450 (M+), 432, 391, 371, 348.

IR (K8r): 3398 (br), 2932, 2865, 1720 (sh. 1740), 1652, 1.538, 1375, 1265, 1236 cm-1.

NMR (200 MHz 1H, CUC13): ' 60.89, 1.22, 1.99, 2.17 (all s, 3H); 1V0-2.2 (m);
au 2.7 (t, J-13, 1H, H-8); 3.03 (s, 1H, OH-17); 4.2 (br s, 1H, H-11); 4=.3 (br s, 1H, H-3), 4.96 (AB, J=17.5, av=42, 2H, H-21); 5,8 (d, J=10, 1H, NH).

, ~ , ,

Claims (78)

1. CLAIMS:
1. Topical, systemic or intraocular use of a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of:

4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate;
and 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione;
for preventing or treating ocular neovascularization.
2. The use of claim 1, wherein the ocular neovascularization is associated with a condition or disease selected from the group consisting of diabetic retinopathy, chronic glaucoma, retinal detachment, sickle cell retinopathy, senile macular degeneration, rubeosis iritis, uveitis, neoplasms, Fuch's heterochromic iridocyclitis, neovascular glaucoma, corneal neovascularization, neovascularization resulting from combined vitrectomy and lensectomy, retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, carotid artery ischemia, pterigium and contusive ocular injury.
3. The use of claim 1 or 2, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate.
4. The use of claim 1 or 2, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione.
5. The use of any one of claims 1 to 4, wherein the angiostatic steroid is for administration at a concentration of about 0.01 to 10.0 weight percent.
6. The use of any one of claims 1 to 4, wherein the angiostatic steroid is for administration at a concentration of about 0.1 to 5.0 weight percent.
7. The use of any one of claims 1 to 6, wherein the use is the intraocular use.
8. A commercial package comprising a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of:

4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-2l-acetate;
and 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione;
together with instructions for the use thereof for preventing or treating ocular neovascularization.
9. Topical, systemic or intraocular use of a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of:

4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate;
and 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione;
for preventing or treating ocular neovascularization of a tissue in the front or the back of an eye of a host.
10. The use of claim 9, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate.
11. The use of claim 9, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione.
12. The use of any one of claims 9 to 11, wherein the angiostatic steroid is for administration at a concentration of about 0.01 to 10.0 weight percent.
13. The use of any one of claims 9 to 11, wherein the angiostatic steroid is for administration at a concentration of about 0.1 to 5.0 weight percent.
14. The use of any one of claims 9 to 13, wherein the tissue is in the front of the eye.
15. The use of claim 14, wherein the tissue is a cornea.
16. The use of any one of claims 9 to 13, wherein the tissue is in the back of the eye.
17. The use of claim 16, wherein the tissue is a retina or subretina.
18. The use of claim 16, wherein the tissue is a macula.
19. The use of claim 16, wherein the tissue is an optic nerve head.
20. The use of any one of claims 9 to 19, wherein the use is the intraocular use.
21. A commercial package comprising a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of:

4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate;
and 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione;

together with instructions for the use thereof use for preventing or treating ocular neovascularization of a tissue in the front or the back of an eye of a host.
22. Use of a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of:
4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate;
and 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione;
in preparation of a pharmaceutical composition for topical, systemic or intraocular administration for preventing or treating ocular neovascularization.
23. The use of claim 22, wherein the ocular neovascularization is associated with a condition or disease selected from the group consisting of diabetic retinopathy, chronic glaucoma, retinal detachment, sickle cell retinopathy, senile macular degeneration, rubeosis iritis, uveitis, neoplasms, Fuch's heterochromic iridocyclitis, neovascular glaucoma, corneal neovascularization, neovascularization resulting from combined vitrectomy and lensectomy, retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, carotid artery ischemia, pterigium and contusive ocular injury.
24. The use of claim 22 or 23, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate.
25. The use of claim 22 or 23, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione.
26. The use of any one of claims 22 to 25, wherein the angiostatic steroid is for administration at a concentration of about 0.01 to 10.0 weight percent.
27. The use of any one of claims 22 to 25, wherein the angiostatic steroid is for administration at a concentration of about 0.1 to 5.0 weight percent.
28. The use of any one of claims 22 to 27, wherein the use is the intraocular use.
29. An angiostatic steroid selected from the group consisting of:

4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate;
and 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione;
for topical, systemic or intraocular administration for preventing or treating ocular neovascularization.
30. The steroid of claim 29, wherein the ocular neovascularization is associated with a condition or disease selected from the group consisting of diabetic retinopathy, chronic glaucoma, retinal detachment, sickle cell retinopathy, senile macular degeneration, rubeosis iritis, uveitis, neoplasms, Fuch's heterochromic iridocyclitis, neovascular glaucoma, corneal neovascularization, neovascularization resulting from combined vitrectomy and lensectomy, retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, carotid artery ischemia, pterigium and contusive ocular injury.
31. The steroid of claim 29 or 30, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate.
32. The steroid of claim 29 or 30, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione.
33. The steroid of any one of claims 29 to 32, wherein the angiostatic steroid is for administration at a concentration of about 0.01 to 10.0 weight percent.
34. The steroid of any one of claims 29 to 32, wherein the angiostatic steroid is for administration at a concentration of about 0.1 to 5.0 weight percent.
35. The steroid of any one of claims 29 to 34, wherein the administration is the intraocular administration.
36. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of:

4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-2l-acetate;
and 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione;
for topical, systemic or intraocular administration for preventing or treating ocular neovascularization.
37. The pharmaceutical composition of claim 36, wherein the ocular neovascularization is associated with a condition or disease selected from the group consisting of diabetic retinopathy, chronic glaucoma, retinal detachment, sickle cell retinopathy, senile macular degeneration, rubeosis iritis, uveitis, neoplasms, Fuch's heterochromic iridocyclitis, neovascular glaucoma, corneal neovascularization, neovascularization resulting from combined vitrectomy and lensectomy, retinal ischemia, choroidal vascular insufficiency, choroidal thrombosis, carotid artery ischemia, pterigium and contusive ocular injury.
38. The pharmaceutical composition of claim 36 or 37, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate.
39. The pharmaceutical composition of claim 36 or 37, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione.
40. The pharmaceutical composition of any one of claims 36 to 39, wherein the angiostatic steroid is for administration at a concentration of about 0.01 to 10.0 weight percent.
41. The pharmaceutical composition of any one of claims 36 to 39, wherein the angiostatic steroid is for administration at a concentration of about 0.1 to 5.0 weight percent.
42. The pharmaceutical composition of any one of claims 36 to 41, wherein the administration is the intraocular administration.
43. Use of a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of:
4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate;
and 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione;
in preparation of a pharmaceutical composition for topical, systemic or intraocular administration for preventing or treating ocular neovascularization of a tissue in the front or the back of an eye of a host.
44. The use of claim 43, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate.
45. The use of claim 43, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione.
46. The use of any one of claims 43 to 45, wherein the angiostatic steroid is for administration at a concentration of about 0.01 to 10.0 weight percent.
47. The use of any one of claims 43 to 45, wherein the angiostatic steroid is for administration at a concentration of about 0.1 to 5.0 weight percent.
48. The use of any one of claims 43 to 47, wherein the tissue is in the front of the eye.
49. The use of claim 48, wherein the tissue is a cornea.
50. The use of any one of claims 43 to 47, wherein the tissue is in the back of the eye.
51. The use of claim 50, wherein the tissue is a retina or subretina.
52. The use of claim 50, wherein the tissue is a macula.
53. The use of claim 50, wherein the tissue is an optic nerve head.
54. The use of any one of claims 43 to 53, wherein the administration is the intraocular administration.
55. An angiostatic steroid selected from the group consisting of:

4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate;
and 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione;
for topical, systemic or intaocular administration for preventing or treating ocular neovascularization of a tissue in the front or the back of an eye of a host.
56. The steroid of claim 55, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate.
57. The steroid of claim 55, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione.
58. The steroid of any one of claims 55 to 57, wherein the angiostatic steroid is for administration at a concentration of about 0.01 to 10.0 weight percent.
59. The steroid of any one of claims 55 to 57, wherein the angiostatic steroid is for administration at a concentration of about 0.1 to 5.0 weight percent.
60. The steroid of any one of claims 55 to 59, wherein the tissue is in the front of the eye.
61. The steroid of claim 60, wherein the tissue is a cornea.
62. The steroid of any one of claims 55 to 59, wherein the tissue is in the back of the eye.
63. The steroid of claim 62, wherein the tissue is a retina or subretina.
64. The steroid of claim 62, wherein the tissue is a macula.
65. The steroid of claim 62, wherein the tissue is an optic nerve head.
66. The steroid of any one of claims 55 to 65, wherein the administration is the intraocular administration.
67. A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and a pharmaceutically effective amount of an angiostatic steroid selected from the group consisting of:

4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate;
and 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione;
for topical, systemic or intaocular administration for preventing or treating ocular neovascularization of a tissue in the front or the back of an eye of a host.
68. The pharmaceutical composition of claim 67, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione-21-acetate.
69. The pharmaceutical composition of claim 67, wherein the angiostatic steroid is 4,9(11)-Pregnadien-17.alpha.,21-diol-3,20-dione.
70. The pharmaceutical composition of any one of claims 67 to 69, wherein the angiostatic steroid is for administration at a concentration of about 0.01 to 10.0 weight percent.
71. The pharmaceutical composition of any one of claims 67 to 69, wherein the angiostatic steroid is for administration at a concentration of about 0.1 to 5.0 weight percent.
72. The pharmaceutical composition of any one of claims 67 to 71, wherein the tissue is in the front of the eye.
73. The pharmaceutical composition of claim 72, wherein the tissue is a cornea.
74. The pharmaceutical composition of any one of claims 67 to 71, wherein the tissue is in the back of the eye.
75. The pharmaceutical composition of claim 74, wherein the tissue is a retina or subretina.
76. The pharmaceutical composition of claim 74, wherein the tissue is a macula.
77. The pharmaceutical composition of claim 74, wherein the tissue is an optic nerve head.
78. The pharmaceutical composition of any one of claims 67 to 77, wherein the administration is the intraocular administration.
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